No-synthase inhibitors

ABSTRACT

The use of an effective amount of at least one nitric oxide synthase inhibitor in a cosmetic composition or for making a pharmaceutical composition is disclosed, said inhibitor or pharmaceutical composition being intended to reduce the skin irritant effect of topically applied cosmetic or pharmaceutical substances. A cosmetic or pharmaceutical composition containing an effective amount of at least one nitric oxide synthase inhibitor, and a cosmetic treatment method using said cosmetic composition, are also disclosed.

The present invention relates to a use of an effective quantity of atleast one NO-synthase inhibitor in a cosmetic composition or for themanufacture of a pharmaceutical composition, this inhibitor or thepharmaceutical composition being intended to reduce the cutaneousirritant effect of products used topically in the cosmetic orpharmaceutical field.

It also relates to a cosmetic or pharmaceutical composition comprisingan effective quantity of at least one NO-synthase inhibitor and aprocess of cosmetic treatment using the cosmetic composition accordingto the invention.

Within the framework of the present invention, the cutaneous irritanteffect is a response of the skin which is most often manifested byblotches, pain or pricking, this response being generated by chemicalproducts of natural or synthetic origin which are topically applied tothe skin. This irritation is accompanied by impairment of the epithelialstructure and/or function which is directly linked to the effect of theproduct having an irritant character.

Thus, the disruptions induced by a product having an irritant characterare followed by a response of the skin which is intense to a greater orlesser degree aimed at restoring the homeostatic equilibrium which isbroken or to repair the damages caused. This response may beinfraclinical, that is to say without obvious inflammatory reaction tothe naked eye. However, the reaction which is intense to a greater orlesser degree remains the most usual tissue response to aggressioncaused by an irritant product and the most disturbing for the user ofthis product having an irritant character.

When the product having an irritant character reaches the skin, it canreact with certain pre-existing substances in the cells and the tissuesand/or liberate intracellular substances. These liberated substancesmay, in turn, become active on other targets in the epithelium or thedermis. Thus, begins the cascade of reactions which, through therecruitment of blood cells and the substances which they liberate, giverise to the irritant process which is characterized mainly by irritationof the skin. This process is manifested in particular in variousdegrees, depending mainly on the quality and/or quantity of the productapplied and/or the user of this product, by dysaesthetic sensations(inflammation, burning sensations, itching or pruritus, sensations ofpricking, of twitching and the like), by blotches and/or by an oedema.

These products having an irritant character may be used in cosmetic orpharmaceutical, and more particularly dermatological, compositions quiteobviously for other effects. Thus, they are generally used as activeagents, surfactants, preservatives, perfumes, solvents or propellentsfor the said compositions.

However, because of their irritant character, these products aregenerally used in very low doses. The use of these products in smallquantities may then prove to be of little advantage compared with theuse of other products which are less active but less or not irritant andwhich are therefore used in a larger quantity.

Consequently, there is a need in the cosmetic and pharmaceutical fieldto find a means allowing these products to be used, without the latterexhibiting an irritant character which can be criticized by the user.

Now, the Applicant has discovered that the NO-synthase inhibitors makeit possible to limit, or even suppress, the irritant character of theseproducts.

Thus, the subject of the present invention is the use of an effectivequantity of at least one NO-synthase inhibitor in a cosmetic compositionor for the manufacture of a pharmaceutical composition, this inhibitoror the pharmaceutical composition being intended to reduce the cutaneousirritant effect of products topically used in the cosmetic orpharmaceutical field.

The cosmetic or pharmaceutical composition comprising the NO-synthaseinhibitor may comprise or otherwise the product capable of causing acutaneous irritation.

In the case where these compounds exist in the same composition, thepresent invention also relates to a composition for topical, cosmetic orpharmaceutical use, characterized in that it comprises, in acosmetically or pharmaceutically acceptable medium, an effectivequantity of at least one NO-synthase inhibitor and at least one productcapable of causing cutaneous irritation.

The pharmaceutical composition is preferably a dermatologicalcomposition.

The present invention also relates to a process of cosmetic treatment,characterized in that it uses the cosmetic composition according to theinvention.

The effective quantity of at least one NO-synthase inhibitor accordingto the invention is a sufficient quantity of at least one NO-synthaseinhibitor so that the cutaneous irritant effect decreases or evendisappears. Thus, this quantity is variable depending on the quantityand the nature of the product having an irritant character which isapplied. However, by way of illustration, a composition according to theinvention may comprise at least one NO-synthase inhibitor at aconcentration by weight of between 10⁻⁶% and 10% of the total weight ofthe composition and preferably between 10⁻⁴% and 1% of the total weightof the composition.

In the composition according to the invention, the quantity of theproduct capable of causing a cutaneous irritation may thereforecorrespond to a quantity which is sufficient to cause a cutaneousirritation if it was used alone (without the NO-synthase inhibitor).

Numerous topically applied products exhibit an irritant character,especially for people (users) with easily irritable skins.

Thus, even the products which are considered to be inert in a cosmeticor pharmaceutical, more particularly dermatological, composition mayexhibit an irritant character when they are applied to the skin, thescalp, the nails or the mucous membranes, such as in particularpreservatives, surfactants, perfumes, solvents or propellents.

Accordingly, products considered as active agents in cosmetic orpharmaceutical compositions may exhibit an irritant character when theyare applied to the skin, the scalp, the nails or the mucous membranes,it is possible to speak of a secondary irritant effect, such asespecially some sunscreens, α-hydroxy acids (glycol, lactic, malic,citric, tartaric, mandelic), β-hydroxy acids (salicylic acid and itsderivatives), α-keto acids, β-keto acids, retinoids (retinol and itsesters, retinal, retinoic acid and its derivatives, retinoids,especially those described in the documents FR-A-2,570,377,EP-A-199,636, EP-A-325,540, EP-A-402,072), anthralins (dioxyanthranol),anthranoids (for example those described in the document EP-A-319,028),peroxides (especially benzoyl peroxide), minoxidil and its derivatives,lithium salts, antiproliferative agents, such as 5-fluorouracyl ormethotrexate, some vitamins, such as vitamin D and its derivatives,vitamin B9 and its derivatives, hair dyes or colorants(para-phenylenediamine and its derivatives, aminophenols), perfumingalcoholic solutions (perfumes, toilet water, aftershave, deodorants),antiperspirants (some aluminium salts), depilatory or permanent wavingactive agents (thiols), depigmenting agents (hydroquinone), capsaicin,antilouse active agents (pyrethrin), ionic and nonionic detergent agentsand propigmenting agents (dihydroxyacetone, psoralens andmethylangecilins).

Among these products with a secondary irritant effect, the inventionrelates more particularly to retinoids.

Among the retinoids, there may be mentioned more particularlyall-trans-retinoic acid, 13-cis-retinoic acid,2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid sold underthe name Adapalène™ by the company Galderma, Tazarotène™, having thegeneric chemical name,6-[(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethylnyl]-3-pyridinecarboxylicacid ethyl ester, sold by the company Allergan.

Among the vitamin D and its derivatives, there may be mentioned moreparticularly vitamin D₃, vitamin D₂, 1,25-diOH vitamin D₃ (calcitriol),calcipotriol, 1,24-diOH vitamin D₃ (such as tacalcitol), 24,25-diOHvitamin D₃, 1-OH vitamin D₂, 1,24-diOH vitamin D₂.

Among the salicylic acid derivatives, there may be mentioned moreparticularly 5-n-octanoyl-salicylic acid and 5-n-dodecanoylsalicylicacid or their esters.

The nitrogen monoxide (NO) is enzymatically generated by L-arginine, theenzyme being called NO-synthase.

The NO-synthase inhibitors are, according to the invention, productswhich make it possible in situ, in man, to partially or even completelyinhibit the synthesis of nitrogen monoxide (NO).

This enzyme exists in two forms, the constitutive form and the inducibleform (Medecine/Sciences, 1992, 8, pp. 843–845). Among the inhibitors,use of the inhibitors of constitutive NO-synthase is preferred, that isto say the inhibitors which inhibit the constitutive NO-synthase equallyor more compared with the inducible NO-synthase. The tests to identifythe inhibitors of constitutive or inducible NO-synthase are described inparticular in U.S. Pat. No. 5,132,453.

Among these inhibitors of constitutive NO-synthase, the inhibitors ofendothelial NO-synthase are preferred.

Indeed, it seems, without wishing to be tied to any theory of theinvention, that the reduction in irritation observed in the presentinvention is due mainly to the inhibition of the constitutiveNO-synthases, and more particularly to the inhibition of the NO-synthaseof the endothelial cells.

Thus, among these inhibitors of the constitutive NO-synthase, there maybe mentioned more particularly N^(G)-monomethyl-L-arginine (NMMA), themethyl ester of N^(G)-nitro-L-arginine (NAME), N^(G)-nitro-L-arginine(NNA), N^(G)-amino-L-arginine (NAA), N^(G),N^(G)-dimethylarginine(asymmetric dimethylarginine, called ADMA).

NMMA, NAME, NNA and ADMA are preferably used.

The inhibitors of NO-synthase may be used alone or as a mixture.

The inhibitors of NO-synthase may be used both for preventive andcurative purposes.

The present invention has in particular the advantage of being able toincrease the quantity of active agents having an irritant character incosmetic or pharmaceutical compositions compared with the quantitynormally used, for an enhanced efficacy of the said active agents. Thus,the hydroxy acids may be used up to 50% of the weight of the compositionor the retinoids up to 5%, without any inconvenience for the user.

The NO-synthase inhibitor(s) may be used by the enteral, parenteral ortopical route.

By the topical route, direct application to the skin, the scalp, thenails or the mucous membranes is preferred.

The compositions according to the invention may be provided in anygalenic form. These compositions are prepared according to the customarymethods.

A cosmetically or dermatologically acceptable medium generallycorresponds to a medium which is compatible with the skin, the scalp,the nails or the mucous membranes. The composition comprising theNO-synthase inhibitor may therefore be applied to the face, the neck,the hair and the nails, or any other cutaneous zone of the body(axillary or submammary regions, the elbow bend and the like).

By the topical route, the compositions according to the invention areprovided especially in the form of aqueous, aqueous-alcoholic or oilysolutions, of dispersions of the lotion or serum type, of anhydrous orlipophilic gels, of emulsions of liquid or semi-liquid consistency ofthe milk type, obtained by dispersion of a fatty phase in an aqueousphase (O/W) or conversely (W/o), or of suspensions or emulsions of soft,semi-solid or solid consistency of the cream or gel type, or ofmicroemulsions, microcapsules, microparticles or vesicular dispersionsof the ionic and/or nonionic type. These compositions are preparedaccording to the customary methods.

By the enteral route, the compositions according to the invention may beprovided in the form of tablets, gelatin capsules, sugar-coated tablets,syrups, suspensions, solutions, powders, granules, emulsions,microspheres or nanospheres or lipid or polymeric vesicles which allow acontrolled release.

By the parenteral route, the compositions may be provided in the form ofsolutions or suspensions for infusion or injection.

They may also be used on the scalp in the form of aqueous, alcoholic oraqueous-alcoholic solutions, or in the form of creams, gels, emulsions,foams or in the form of compositions for an aerosol also containing apressurized propelling agent.

The quantities of the various constituents of the compositions accordingto the invention are those conventionally used in the fields considered.

These compositions constitute in particular shaving foams, cleansing,protective, treatment or care creams for the face, for the hands, forthe feet, for the large anatomical folds or for the body, (for exampleday creams, night creams, make-up removing creams, foundation creams,antisun creams), fluid foundations, make-up removing milks, protectiveor care body milks, antisun or better still after-sun milks, skin carelotions, gels or foams, such as lotions for cleansing or disinfection,antisun lotions, artificial tanning lotions, bath compositions,deodorant compositions containing a bactericidal agent, aftershave gelsor lotions, depilatory creams, compositions against insect bites,antipain compositions or compositions for treating certain skin diseasessuch as those mentioned above.

The compositions according to the invention may also consist of solidpreparations constituting cleansing soaps or cakes.

The compositions may also be packaged in the form of an aerosolcomposition also containing a pressurized propelling agent.

The NO-synthase inhibitors may also be incorporated into variouscompositions for hair care or treatments, especially shampoos which areoptionally antiparasitic, hair setting lotions, treatment lotions, hairstyling creams or gels, dyeing (especially oxidation dyeing)compositions optionally in the form of dyeing shampoos, restructuringlotions for the hair, permanent waving compositions (especiallycompositions for the first stage of a permanent waving), lotions or gelsagainst hair loss, and the like.

The compositions of the invention may also be for dentibuccal use, forexample a toothpaste or a mouthwash. In this case, the compositions maycontain customary adjuvants and additives for compositions for buccaluse and especially surfactants, thickening agents, humectants, polishingagents such as silica, various active ingredients such as fluorides, inparticular sodium fluoride, and optionally sweetening agents such assodium saccharinate.

When the composition of the invention is an emulsion, the proportion offatty phase may range from 5% to 80% by weight, and preferably from 5%to 50% by weight relative to the total weight of the composition. Theoils, emulsifiers and coemulsifiers used in the composition in the formof an emulsion are chosen from those conventionally used in the cosmeticand pharmaceutical fields. The emulsifier and the coemulsifier arepresent in the composition in a proportion ranging from 0.3% to 30% byweight, and preferably from 0.5 to 30% or better still from 0.5 to 20%by weight relative to the total weight of the composition. The emulsionmay, in addition, contain lipid vesicles.

When the composition of the invention is an oily gel or a solution, thefatty phase may represent more than 90% of the total weight of thecomposition.

In a known manner, the composition of the invention may also containadjuvants common in the cosmetic or pharmaceutical field, such ashydrophilic or lipophilic gelling agents, hydrophilic or lipophilicactive agents, preservatives, antioxidants, solvents, perfumes, fillers,screening agents, bactericides, odour absorbers and colouring matter.The quantities of these various adjuvants are those conventionally usedin the cosmetic or pharmaceutical field, and for example from 0.01% to10% of the total weight of the composition. These adjuvants, dependingon their nature, may be introduced into the fatty phase, into theaqueous phase and/or into the lipid spherules.

As oils which can be used in the invention, there may be mentionedmineral oils (petroleum jelly), vegetable oils (liquid fraction of sheabutter, sunflower oil), animal oils (perhydrosqualene), synthetic oils(Purcellin oil), silicone oils (cyclomethicone) and fluorinated oils(perfluoropolyethers). There may also be used, as fatty substances,fatty alcohols, fatty acids (stearic acid), waxes (paraffin, carnauba,beeswax).

As emulsifiers which can be used in the invention, there may bementioned for example glycerol stearate, polysorbate 60 and thePEG-6/PEG-32/Glycol Stearate mixture sold under the name Tefose® 63 bythe company Gattefosse.

As solvents which can be used in the invention, there may be mentionedthe lower alcohols, especially ethanol and isopropanol, propyleneglycol.

As hydrophilic gelling agents, there may be mentioned the carboxyvinylpolymers (carbomer), acrylic copolymers such as acrylate/alkylacrylatecopolymers, polyacrylamides, polysaccharides such ashydroxypropylcellulose, natural gums and clays, and, as lipophilicgelling agents, there may be mentioned modified clays such as bentones,metal salts of fatty acids such as aluminium stearates and hydrophobicsilica, or ethylcellulose, polyethylene.

As hydrophilic active agents, there may be used proteins or proteinhydrolysates, amino acids, polyols, urea, allantoin, sugars and sugarderivatives, water-soluble vitamins, starch and plant extracts,especially those of aloe vera.

As lipophilic active agents, there may be used retinol (vitamin A) andits derivatives, tocopherol (vitamin E) and its derivatives, essentialfatty acids, ceramides, essential oils.

The NO-synthase inhibitors may, inter alia, be combined with activeagents intended especially for the prevention and/or treatment of skinconditions. Among these active agents, there may be mentioned, by way ofexample:

agents modulating skin differentiation and/or proliferation and/orpigmentation such as especially retinoids, vitamin D and itsderivatives, oestrogens such as estradiol, kojic acid or hydroquinone;

antibacterials such as clindamycin phosphate, erythromycin orantibiotics of the tetracycline class;

antiparasitic agents, in particular metronidazole, crotamiton orpyrethrinoids;

antifungal agents, in particular the compounds belonging to theimidazole class such as econazole, ketoconazole or miconazole or theirsalts, the polyene compounds, such as amphotericin B, the compounds ofthe allylamine family, such as terbinafine, or octopirox;

steroidal anti-inflammatory agents such as hydrocortisone, betamethasonevalerate or clobetasol propionate, or nonsteroidal anti-inflammatoryagents such as ibuprofen and its salts, diclofenac and its salts,acetylsalicylic acid, acetaminophen or glycyrrhetinic acid;

anaesthetic agents such as lidocaine hydrochloride and its derivatives;

antipruriginous agents such as thenaldine, trimeprazine orcyproheptadine;

antiviral agents such as acyclovir;

keratolytic agents such as alpha- and beta-hydroxycarboxylic orbeta-ketocarboxylic acids, their salts, amides or esters and moreparticularly alpha-hydroxy acids such as glycolic acid, lactic acid,tartaric acid, citric acid and, in general, fruit acids and beta-hydroxyacids such as salicylic acid and its derivatives, especially alkylatedderivatives, such as 5-n-octanoylsalicylic acid;

anti-free radical agents, such as alpha-tocopherol or its esters,superoxide dismutases, certain metal chelators or ascorbic acid and itsesters;

antiseborrhoeic agents such as progesterone;

antidandruff agents such as octopirox or zinc pyrithione;

anti-acne agents such as retinoic acid or benzoyl peroxide.

Of course persons skilled in the art will be careful to choose thepossible compound(s) present in the composition according to theinvention so that the properties intrinsically linked to the presentinvention are not, or not substantially, altered.

The pharmaceutical compositions according to the invention areparticularly suitable in the following fields of treatment, thesetreatments being particularly appropriate when these compositionscomprise retinoids:

1) for treating dermatological conditions linked to a keratinizationdisorder related to differentiation and proliferation especially totreat acne vulgaris, comedo-type acne, polymorphic acne, rosacea,nodulocystic acne, acne conglobata, senile acne, secondary acne such assolar acne, acne medicamentosa or occupational acne,

2) for treating other types of keratinization disorders, especiallyichthyosis, ichthyosiform states, Darier's disease, keratosis palmariset plantaris, leukoplasia and leukoplasiform states, cutaneous ormucosal (buccal) lichen,

3) for treating other dermatological conditions linked to akeratinization disorder with an inflammatory and/or immunoallergiccomponent, and especially all the forms of psoriasis, whether cutaneous,mucosal or ungual, and even psoriatic rheumatism, or cutaneous atopy,such as eczema or respiratory atopy or gingival hypertrophy; thecompounds may also be used in certain inflammatory conditions which donot exhibit keratinization disorder,

4) for treating any dermal or epidermal proliferations whether benign ormalignant, whether of viral origin or not, such as verruca vulgaris,verruca plana and epidermodysplasia verruciformis, oral or floridpapillomatoses and proliferations which may be induced by ultravioletradiation especially in the case of baso- and spinocellular epithelioma,

5) for treating other dermatological disorders such as bullousdermatoses and collagen diseases,

6) for treating certain ophthalmological disorders, especiallycorneopathies,

7) for repairing or combating skin ageing, whether photoinduced orchronologic, or for reducing pigmentations and actinic keratoses, or anypathologies associated with chronologic or actinic ageing,

8) for preventing or curing the stigmas of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof cutaneous atrophy,

9) for preventing or treating cicatrization disorders or preventing orrepairing vibices,

10) for combating disorders of the sebaceous function, such ashyperseborrhoea of acne or simple seborrhoea,

11) in the treatment or prevention of cancerous or precancerous states,

12) in the treatment of inflammatory conditions such as arthritis,

13) in the treatment of any condition of viral origin at the cutaneouslevel or in general,

14) in the prevention or treatment of alopecia,

15) in the treatment of dermatological or general conditions with animmunological component,

16) in the treatment of conditions of the cardiovascular system, such asarteriosclerosis.

The subject of the present invention is, in addition, a process ofcosmetic treatment, characterized in that it uses the cosmeticcomposition according to the invention.

Preferably, the process of cosmetic treatment consists in applying tothe skin, the scalp and/or the mucuous membranes a composition asdescribed above.

The process of cosmetic treatment of the invention can be carried out inparticular by applying the hygiene or cosmetic compositions as definedabove, according to the usual technique for using these compositions.For example: application of creams, gels, sera, lotions, make-upremoving milks or after-sun compositions to the skin or to dry hair,application of a hair lotion to wet hair, of shampoo or application oftoothpaste to the gums.

In the cosmetic field, the compositions according to the invention aresuitable, depending on the active agents contained in this composition,in particular in body and hair hygiene and especially for the treatmentof skins which tend to have acne, for hair regrowth, against hair loss,for combating the greasy appearance of the skin or the hair, inprotection against the harmful aspects of the sun or in the treatment ofphysiologically dry skins, for preventing and/or for combatingphoto-induced or chronologic ageing.

Several examples for obtaining active compounds of formula (I) accordingto the invention, as well as various concrete formulations based on suchcompounds will now be given by way of illustration and with nolimitation being implied.

EXAMPLE 1

The aim of this example is to demonstrate the oral anti-irritantactivity in vivo of the methyl ester of N^(G)-nitro-L-arginine used forcurative purposes.

The test used to evaluate this activity is that of mouse ear oedema(Balb/C mouse) induced by topical application of 0.01% by weight of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid. According to this model, the response to a topical application of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid to the ear results in an increase in the thickness of the ear whichis maximum 5 days after the application. This increase in the thicknessof the mouse ear appears to be due to an increase in the thickness ofthe epidermis and to the appearance of a dermal oedema. This responsecan therefore be easily measured with the aid of an apparatus, such asthe oditest.

The exact operating procedure is the following: 10 mice are firsttreated with the active product having an irritant character bytopically applying to one of their ears at time t=0 with 20 μl of anacetone solution containing 0.01% by weight of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid. 5 (=group 2) of the 10 mice thus treated are made to ingest orallyN^(G)-nitro-L-arginine methyl ester in drinking water from t=0 and onceper day for 11 days (N^(G)-nitro-L-arginine methyl ester concentrationof 1 mg/ml, that is to say 170±40 mg/kg per day). The 5 mice which didnot ingest the N^(G)-nitro-L-arginine methyl ester constitute group 1.The oedematous response is quantified by measurement of the thickness ofthe ear. The results are then expressed as % increase in the thicknessof the mouse ear compared to the increase in thickness observed on theother ear which, for its part, was treated (under the same conditions asabove) with only an acetone solution without active agent (control orreference ear).

The results obtained are as follows:

After 5 days of treatment, the increase in the thickness of the mouseear is at its maximum (100%) for group 1 and is 70% for group 2.

The above results clearly demonstrate a 30% inhibition of the ear oedemafor the mice treated with this NO-synthase inhibitor.

Furthermore, no sign of toxicity was observed and the change in weightwas not modified in the mice treated with this inhibitor.

EXAMPLE 2

The aim of this example is to demonstrate the topical anti-irritantactivity in vivo of N^(G),N^(G)-dimethylarginine administered forpreventive purposes.

The test used to evaluate this activity is the same as that used inExample 1.

The exact operating procedure is the following: 5 mice are first treatedwith a gel comprising, as sole active agent, 1% by weight ofN^(G),N^(G)-dimethylarginine by one topical application per day to oneof their ears for 4 days. No increase in the thickness of the ear of themice thus treated is observed. Next, there is topically applied to theear of these 5 mice previously treated with N^(G),N^(G)-dimethylarginine(group A) and to the ear of 5 untreated mice (group B), at time t=0, 20μl of an acetone solution comprising 0.01% by weight of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid. The oedematous response is quantified by measurement of thethickness of the ear. The results are then expressed as % increase inthe thickness of the mouse ear compared with the increase in thicknessobserved on the other ear which, for its part, was treated (under thesame conditions as above), with only an acetone solution without activeagent (control or reference ear and oedema).

By comparing groups A and B, the results obtained are the following:

N^(G),N^(G)-dimethylarginine applied topically once per day for 4 daysbefore the application of the product having an irritant character(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid) reduces by 24% the amplitude and by 50% the area under the curveof the response induced by the product having an irritant character (thecurve corresponding to the thickness of the ear as a function of thedays for the reading).

EXAMPLE 3

The aim of this example is to demonstrate the topical anti-irritantactivity in vivo of N^(G)-monomethyl-L-arginine (L-NMMA) used forcurative purposes.

The test used to evaluate this activity is the same as that used inExample 1.

The exact operating procedure is the following: 10 mice are firsttreated with the active product having an irritant character bytopically applying to one of their ears at time t=0 with 20 μl of anacetone solution containing 0.01% by weight of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid. A gel comprising 1% by weight of L-NMMA is topically applied to 5(=group 2) of the 10 mice thus treated 6 hours after the application ofthe product having an irritant character, once per day for 5 days. The 5mice which were not treated with L-NMMA constitute group 1. Theoedematous response is quantified by measurement of the thickness of theear. The results are then expressed as % increase in the thickness ofthe mouse ear compared to the increase in thickness observed on theother ear which, for its part, was treated (under the same conditions asabove) with only an acetone solution without active agent (control orreference ear).

The results obtained are as follows:

After 5 days of treatment, the increase in the thickness of the mouseear is at its maximum (100%) for group 1 and is 72% for group 2.

The results clearly demonstrate a 28% inhibition of the ear oedema forthe mice treated with this NO-synthase inhibitor.

L-NMMA reduces by 51% the area under the curve of the response inducedby the product having an irritant character (the curve corresponding tothe thickness of the ear as a function of the days for the reading).

If the same treatment is carried out by applying, in place of L-NMMA, 1%or 5% betaine or 1% N^(G),N^(G)-dimethyl-L-arginine (symmetricdimethyl-L-arginine, called SDMA), a 9, 16 and 7% inhibition of theoedema of the ear is observed, respectively, for the mice treated withthese products which are not NO-synthase inhibitors (see especially forSDMA: The Lancet, Vol. 339: 572–575). A 24, 13 and 27% reduction in thearea under the curve of the response induced by the product having anirritant character is also observed respectively (the curvecorresponding to the thickness of the ear as a function of the days forthe reading).

EXAMPLE 4

Compositions in accordance with the invention, provided in the form of alotion, a gel and a cream for topical use, are illustrated here.

% by weight LOTION Disodium EDTA 0.1 Poloxamer 182 0.2 Water qs 100Ethoxydiglycol 5 N^(G), N^(G)-dimethylarginine 1 GEL Disodium EDTA 0.1Poloxamer 182 0.2 Water qs 100 Sepigel 305 sold by Seppic 3Ethoxydiglycol 5 N^(G), N^(G)-dimethylarginine 1 CREAM Disodium EDTA 0.1Poloxamer 182 0.2 Water qs 100 Preservatives 0.3 Sepigel 305 sold bySeppic 3 Apricot kernel oil 10 Cyclomethicone 5 Ethoxydiglycol 5 Methylester of N^(G)-nitro-L-arginine 1 CREAM oil-in-water emulsionN^(G)-monomethyl-L-arginine (NMMA) 10⁻² Glycerol stearate 2.00Polysorbate 60 (Tween 60 sold by the company ICI) 1.00 Stearic acid 1.40Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of shea butter 12.00Perhydrosqualene 12.00 Antioxidant 0.05 Perfume 0.50 Preservative 0.30Water qs 100 LOTION Adapalène ™ 0.010 g N^(G)-monomethyl-L-arginine(NMMA) 0.100 g Polyethyleneglycol (PEG 400) 69.890 g Ethanol 95% 30.000g

1. A cosmetic or pharmaceutical composition, said compositioncomprising, in a cosmetically or pharmaceutically acceptable medium, atleast one cosmetic or pharmaceutical product capable of causing acutaneous irritant effect, and at least one topically applied nitricoxide synthase inhibitor, wherein said at least one topically appliednitric oxide synthase inhibitor is present in an amount effective toreduce the cutaneous irritant effect of said at least one cosmetic orpharmaceutical product.
 2. A composition according to claim 1, whereinsaid pharmaceutical composition is a dermatological composition.
 3. Acomposition according to claim 1, wherein said at least one nitric oxidesynthase inhibitor is present in a concentration ranging from 10⁻⁶% to10% by weight relative to the total weight of the composition.
 4. Acomposition according to claim 3, wherein said at least one nitric oxidesynthase inhibitor is present in a concentration ranging from 10⁻⁴% to1% by weight relative to the total weight of the composition.
 5. Acomposition according to claim 1, wherein said at least one cosmetic orpharmaceutical product is a preservative, a surfactant, a perfume, asolvent or a propellent.
 6. A composition according to claim 5, whereinsaid at least one cosmetic or pharmaceutical product is a sunscreen, anα-hydroxy acid, a β-hydroxy acid, an α-keto acid, a β-keto acid, aretinoid, an anthralin, an anthranoid, a peroxide, minoxidil or one ofits derivatives, a lithium salt, an antiproliferative agent, vitamin Dor one of its derivatives, vitamin B9 or one of its derivatives, a hairdye, a hair colorant, capsaicin, a perfuming alcoholic solution, anantiperspirant, a depilatory waving active agent, a permanent wavingactive agent, a depigmenting agent, an antilouse active agent, adetergent or a propigmenting agent.
 7. A composition according to claim6, wherein said β-hydroxy acid is salicylic acid or one of itsderivatives.
 8. A composition according to claim 6, wherein said atleast one cosmetic or pharmaceutical product is a retinoid.
 9. Acomposition according to claim 6, wherein said vitamin D or one of itsderivatives is vitamin D₃, vitamin D₂, 1,25-diOH vitamin D₃,calcipotriol, 1,24-diOH vitamin D₃, 24,25-diOH vitamin D₃, 1-OH vitaminD₂, or 1,24-diOH vitamin D₂.
 10. A composition according to claim 9,wherein said 1,24-diOH vitamin D₃ is tacalcitol.
 11. A compositionaccording to claim 7, wherein said salicylic acid derivative is5-n-octanoylsalicylic acid, 5-n-dodecanoylsalicylic acid or one of theiresters.
 12. A composition according to claim 1, wherein said at leastone nitric oxide synthase inhibitor is an inhibitor of constitutivenitric oxide synthase.
 13. A composition according to claim 12, whereinsaid inhibitor of constitutive nitric oxide synthase is an inhibitor ofendothelial nitric oxide synthase.
 14. A composition according to claim12, wherein said at least one nitric oxide synthase inhibitor isN^(G)-monomethyl-L-arginine, the methyl ester of N^(G)-nitro-L-arginine,N^(G)-nitro-L-arginine, N^(G)-amino-L-arginine, or N^(G),N^(G)-dimethylarginine.
 15. A composition according to claim 14, whereinsaid at least one nitric oxide synthase inhibitor is the methyl ester ofN^(G)-nitro-L-arginine, N^(G), N^(G)-dimethylarginine,N^(G)-nitro-L-arginine or N^(G)-monomethyl-L-arginine.
 16. A compositionaccording to claim 1, wherein said composition is formulated in order tobe applied topically to the skin, the scalp or the mucous membranes. 17.A method of reducing the cutaneous irritant effect of a topicallyapplied cosmetic or pharmaceutical composition containing at least onecosmetic or pharmaceutical product capable of having an irritantcharacter on the skin, the scalp, the nails or the mucous membranes,said method comprising applying said cosmetic or pharmaceutical productto said skin, scalp, nails or mucous membranes, wherein said cosmetic orpharmaceutical composition further comprises at least one nitric oxidesynthase inhibitor in an amount effective to reduce the cutaneousirritant effect of said at least one cosmetic or pharmaceutical product.18. A method according to claim 17, wherein said at least one nitricoxide synthase inhibitor is present in a concentration ranging from10⁻⁶% to 10% by weight relative to the total weight of the composition.19. A method according to claim 18, wherein said at least one nitricoxide synthase inhibitor is present in a concentration ranging from10⁻⁴% to 1% by weight relative to the total weight of the composition.20. A method according to claim 19, wherein said at least one cosmeticor pharmaceutical product is a preservative, a surfactant, a perfume, asolvent or a propellent.
 21. A method according to claim 17, whereinsaid at least one cosmetic or pharmaceutical product is a sunscreen, anα-hydroxy acid, a β-hydroxy acid, an α-keto acid, β-keto acid, aretinoid, an anthralin, an anthranoid, a peroxide, minoxidil or one ofits derivatives, a lithium salt, an antiproliferative agent, vitamin Dor one of its derivatives, vitamin B9: or one of its derivatives, a hairdye, a hair colorant, capsaicin, a perfuming alcoholic solution, anantiperspirant, a depilatory waving active agent, a permanent wavingactive agent, a depigmenting agent, an antilouse alive agent, adetergent or a propigmenting agent.
 22. A method according to claim 21,wherein said β-hydroxy acid is salicylic acid or one of its derivatives.23. A method according to claim 21, wherein said at least one cosmeticor pharmaceutical product is a retinoid.
 24. A method according to claim21, wherein said vitamin D or one of its derivatives is vitamin D₃,vitamin D₂, 1,25-diOH vitamin D₃, calcipotriol, 1,24-diOH vitamin D₃,24,25-diOH vitamin D₃, 1-OH vitamin D₂ or 1,24-diOH vitamin D₂.
 25. Amethod according to claim 24, wherein said 1,24-diOH vitamin D₃ istacalcitol.
 26. A method according to claim 22, wherein said salicylicacid derivative is 5-n-octanoylsalicylic acid, 5-n-dodecanoylsalicylicacid or one of their esters.
 27. A method according to claim 17, whereinsaid at least one nitric oxide synthase inhibitor is an inhibitor ofconstitutive nitric oxide synthase.
 28. A method according to claim 27,wherein said inhibitor of constitutive nitric oxide synthase is aninhibitor of endothelial nitric oxide synthase.
 29. A method accordingto claim 27, wherein said at least one nitric oxide synthase inhibitoris N^(G)-monomethyl-L-arginine, the methyl ester ofN^(G)-nitro-L-arginine, N^(G)-nitro-L-arginine, N^(G)-amino-L-arginine,or N^(G),N^(G)-dimethylarginine.
 30. A method according to claim 29,wherein said at least one nitric oxide synthase inhibitor is the methylester of N^(G)-nitro-L-arginine, N^(G), N^(G)-dimethylarginine,N^(G)-nitro-L-arginine or N^(G)-monomethyl-L-arginine.
 31. A process forthe cosmetic treatment of the skin, the scalp, the nails or the mucousmembranes, said process comprising applying a cosmetic compositionaccording to claim 1 to said skin, scalp, nails or mucous membranes. 32.A process for the pharmaceutical treatment of the skin, the scalp, thenails or the mucous membranes, said process comprising applying apharmaceutical composition according to claim 1 to said skin, scalp,nails or mucous membranes.
 33. A composition according to claim 8,wherein said retinoid is all-trans-retinoic acid, 13-cis-retinoic acid,2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid, or6-[(3,4-dihydro4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethylnyl]-3-pyridinecarboxylicacid ethyl ester.
 34. A method according to claim 23, wherein saidretinoid is all-trans-retinoic acid; 13-cis-retinoic acid,2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo[b]thiophenecarboxylicacid, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthanoic acid, or6-[(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethylnyl]-3-pyridinecarboxylicacid ethyl ester.